Non-Coding RNAPub Date : 2026-04-06DOI: 10.3390/ncrna12020013
Mario García-Domínguez
{"title":"Neuropathic Pain: Mapping the miRNA Landscape.","authors":"Mario García-Domínguez","doi":"10.3390/ncrna12020013","DOIUrl":"https://doi.org/10.3390/ncrna12020013","url":null,"abstract":"<p><p>Neuropathic pain represents a complex, prolonged pain state arising from lesions within the somatosensory nervous system. Despite significant advances in elucidating its pathophysiology, current therapeutic approaches remain largely symptomatic and frequently inadequate. MicroRNAs, a class of small non-coding RNAs that regulate gene expression post-transcriptionally, have recently emerged as critical modulators of neuronal excitability, neuroinflammation, and synaptic plasticity, which are crucial processes in the development and maintenance of neuropathic pain. This review summarizes the current evidence linking specific miRNAs to the onset and maintenance of neuropathic pain, with an emphasis on their roles in peripheral and central sensitization. The potential of miRNA-based biomarkers for diagnosis and prognostic evaluation is also highlighted. A thorough understanding of the complex miRNA regulatory networks underlying neuropathic pain could facilitate the development of novel, mechanism-based therapies and ultimately improve clinical outcomes.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-03-31DOI: 10.3390/ncrna12020012
Graham H Read, Kristen McGreevy, Hanny Issawi, Tiffany Yang, Cynthia Tsang, Ihsan A Turk, Emily Rietdorf, Whitaker Cohn, David W Salzman, Julian P Whitelegge, Joanne B Weidhaas
{"title":"Paraspeckles Are Associated with the Activation and Nuclear Localization of Unphosphorylated miR-34a.","authors":"Graham H Read, Kristen McGreevy, Hanny Issawi, Tiffany Yang, Cynthia Tsang, Ihsan A Turk, Emily Rietdorf, Whitaker Cohn, David W Salzman, Julian P Whitelegge, Joanne B Weidhaas","doi":"10.3390/ncrna12020012","DOIUrl":"https://doi.org/10.3390/ncrna12020012","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Canonical microRNAs possess a 5' phosphate required for Argonaute binding and activity. However, prior work identified an unphosphorylated, inactive nuclear pool of the important radiation-responsive microRNA, miR-34, that is rapidly phosphorylated and activated in response to ionizing radiation (IR). Here, we extend this work and investigate the role of paraspeckles, a phase-separated nuclear sub-compartment, and their association with the localization of unphosphorylated miR-34a. <b>Methods:</b> Mass spectrometry was performed to identify interacting partners of unphosphorylated mir-34. CRISPR-mediated deletion of the paraspeckle NEAT1_2 triple helix motif was performed to create an A549 cell line lacking paraspeckles (dTH). Activity and expression of mir-34a post-irradiation were evaluated by qRT-PCR and luciferase assays comparing dTH and wild-type (WT) A549 cell lines. In situ hybridization (ISH) was performed to evaluate mir-34a localization before and after IR, comparing dTH and WT cell lines. <b>Results:</b> Mass spectrometry identified paraspeckle proteins as significantly enriched interacting partners of unphosphorylated mir-34 mimics. By qRT-PCR and luciferase assays, we found that paraspeckle loss prevented radiation-induced early activation of unphosphorylated mir-34a. We found no difference in radiation-induced transcription of pri-miR-34a, but early processing to pre-miR-34a appeared delayed. ISH confirmed that loss of paraspeckles altered the nuclear localization of miR-34a before and after IR. <b>Conclusions:</b> These data suggest that paraspeckles are associated with nuclear localization and early radiation-responsive activation of unphosphorylated miR-34a. This suggests a coordinated nuclear sequestration of this important miR in its unphosphorylated state to enable an enhanced radiation response.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-03-19DOI: 10.3390/ncrna12020011
Francesca Pia Carbone, Stefania Hanau, Nicoletta Bianchi
{"title":"Circular and Long Non-Coding RNAs in Cancer Metabolism: Dual Perspective of Biomarkers and Therapeutic Targets.","authors":"Francesca Pia Carbone, Stefania Hanau, Nicoletta Bianchi","doi":"10.3390/ncrna12020011","DOIUrl":"10.3390/ncrna12020011","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to sustain proliferation, survive under metabolic stress, and develop therapeutic resistance. While oncogenic signaling pathways regulating cancer metabolism have been extensively studied, increasing evidence indicates that non-coding RNAs (ncRNAs) play essential roles in coordinating metabolic adaptation. This review aims to synthesize current knowledge on long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) as important but relatively less characterized regulators of cancer metabolic adaptation and discuss their potential as biomarkers and therapeutic targets. <b>Methods</b>: We analyzed their roles across multiple types of cancer, prioritizing studies that integrate ncRNA profiling with metabolomics and mechanistic investigations, with particular attention to their diagnostic, prognostic, and predictive value. <b>Results</b>: LncRNAs and circRNAs regulate major metabolic pathways, including glycolysis, mitochondrial function, glutaminolysis, lipid metabolism, and redox balance. They act through transcriptional and epigenetic mechanisms, protein scaffolding, peptide encoding, and miRNA sponging, frequently converging on key regulators such as HIF-1α, c-Myc, p53, AMPK, and mTOR. However, many reported associations remain largely correlative, with limited integration of quantitative metabolic flux analyses and insufficient validation in physiologically relevant models. <b>Conclusions</b>: Although lncRNAs and circRNAs constitute an important context-dependent regulatory layer linking oncogenic signaling to metabolic reprogramming, future studies should combine ncRNA perturbation with stable isotope tracing, fluxomics, spatial metabolomics, long-read sequencing, and single-cell approaches to define causal and spatially resolved metabolic functions. Such integrative strategies may improve biomarker development and support ncRNA-informed, metabolism-oriented therapeutic interventions.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-03-16DOI: 10.3390/ncrna12020010
Daniel Angelo R Mirador, Jose Lorenzo M Ferrer, Kim Denyse Hao Lin, Reynaldo L Garcia
{"title":"Vape-Associated lncRNA Transcript 1 (VALT1) Amplifies the Tumorigenic Effects of e-Cigarette Vapor in Lung Epithelial Cells.","authors":"Daniel Angelo R Mirador, Jose Lorenzo M Ferrer, Kim Denyse Hao Lin, Reynaldo L Garcia","doi":"10.3390/ncrna12020010","DOIUrl":"10.3390/ncrna12020010","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Lung cancer remains a major global health burden, largely driven by cigarette use. Although electronic cigarettes (e-cigarettes) are viewed as safer alternatives due to their reduced chemical load, growing evidence shows their vapor can disrupt cellular transcriptomes, including long noncoding RNAs (lncRNAs). In this study, we examined the regulation and function of vape-associated lncRNA transcript 1 (VALT1), a novel transcript upregulated in the oral transcriptomes of e-cigarette users and similarly elevated in non-small-cell lung cancer (NSCLC) tumors. <b>Methods</b>: Publicly available RNA-seq datasets were analyzed, and VALT1 was identified as an e-cigarette-responsive lncRNA. Its dose-dependent induction by e-cigarette smoke extract (eCSE) and cytoplasmic localization were confirmed via RT-qPCR. Its effects on cancer-associated phenotypes including proliferation, ROS detoxification, resistance to apoptosis, migration, cytoskeletal disorganization, and nuclear remodeling were assessed through overexpression and siRNA-mediated knockdown in A549 and BEAS-2B cells. <b>Results</b>: Acute eCSE exposure induced a biphasic, dose-dependent increase in VALT1 expression, accompanied by enhanced proliferation, ROS detoxification, apoptosis resistance, migration, cytoskeletal disorganization, and nuclear remodeling in A549 cells. VALT1 overexpression reproduced these phenotypes in both cell lines without eCSE treatment, whereas knockdown attenuated them. VALT1 promoted survival under cytotoxic stress in A549 but not BEAS-2B cells. <b>Conclusions</b>: These findings support an active role for VALT1 as an e-cigarette vapor-upregulated transcript that contributes to its phenotypic readout and enhances cellular survival under extracellular chemical stress-thereby aggravating tumorigenic phenotypes even in the absence of mutations that contribute to malignant transformation.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-03-12DOI: 10.3390/ncrna12020009
Caio Felipe Freire, Thalles Souza-Lopes, Murilo Sena Amaral, Ana Carolina Tahira, Sergio Verjovski-Almeida
{"title":"Comprehensive <i>Schistosoma mansoni</i> Hierarchical Transcriptome Assembly Points to Novel lncRNAs Associated with Sexual Dimorphism.","authors":"Caio Felipe Freire, Thalles Souza-Lopes, Murilo Sena Amaral, Ana Carolina Tahira, Sergio Verjovski-Almeida","doi":"10.3390/ncrna12020009","DOIUrl":"10.3390/ncrna12020009","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Schistosomiasis is a neglected tropical disease affecting >200 million people worldwide. Praziquantel is the sole recommended drug against <i>Schistosoma mansoni</i>; however, it lacks activity against juvenile forms and cannot prevent reinfection. Thus, there is an urgent need to identify novel therapeutic targets. Long noncoding RNAs (lncRNAs) are known to regulate various biological processes in <i>S. mansoni</i>, including parasite pairing and fertility; therefore, screening for novel lncRNAs could reveal new potential targets. <b>Methods:</b> We compiled all publicly available RNA-seq data from the Sequence Read Archive (SRA) and performed a hierarchical transcriptome assembly using the multi-sample assembler Ryūtō, combined with version 10 of the <i>S. mansoni</i> genome. We applied HOMER for peak-calling and identification of histone marks and used weighted gene co-expression network analysis (WGCNA) to infer putative functions of lncRNAs in sexual dimorphism. <b>Results:</b> Using a robust pipeline, we identified 10,170 novel lncRNA genes comprising 16,990 novel lncRNA transcripts, including 8783 intergenic, 7918 antisense, and 289 intronic lncRNA transcripts. Most (78.7%) have histone regulatory marks (H3K4me3, H3K27me3, H3K27ac, or H4K20me1) near their transcription start sites, indicating potential expression regulation. Comparing male and female samples, we identified 1991 differentially expressed genes (FDR < 5%, |log<sub>2</sub>FC| ≥ 1.5), including 296 known lncRNAs and 339 novel lncRNAs. WGCNA identified hub lncRNAs within co-expression modules, and Gene Ontology enrichment analyses (FDR ≤ 5%) suggest that these lncRNAs are involved in cell differentiation and morphogenesis pathways. <b>Conclusions:</b> We provide a comprehensive catalog of <i>S. mansoni</i> lncRNAs. These findings offer opportunities to discover potential new therapeutic targets, advancing the future development of anti-schistosome therapies.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Short and Long Non-Coding RNAs in Renal Cell Carcinoma.","authors":"Monia Cecati, Valentina Pozzi, Valentina Schiavoni, Giuseppina Barrasso, Veronica Pompei, Daniela Marzioni, Nicoletta Bonci, Stefania Fumarola, Andrea Ballini, Davide Sartini, Roberto Campagna","doi":"10.3390/ncrna12020008","DOIUrl":"10.3390/ncrna12020008","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) represents the most frequent kidney malignancy and remains a major clinical challenge due to its often silent onset, high metastatic potential, and limited responsiveness to conventional chemotherapy. Increasing evidence indicates that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are key regulators of RCC tumorigenesis, progression, and therapy resistance. Rather than providing a purely descriptive overview, this review focuses on emerging mechanistic paradigms through which ncRNAs actively shape tumor behavior and therapeutic response in RCC. This review summarizes current knowledge on the biological and clinical relevance of ncRNAs in RCC, highlighting their dual roles as oncogenic drivers or tumor suppressors through the modulation of pathways involved in proliferation, apoptosis, angiogenesis, invasion, immune evasion, metabolic reprogramming, and ferroptosis. Particular emphasis is placed on mechanistically defined ncRNA regulatory axes controlling ferroptosis, autophagy, metabolic reprogramming, and immune escape, as well as on ncRNA-mediated intercellular communication via extracellular vesicles, which promotes the dissemination of resistance to targeted therapies. The review also addresses ncRNA-based diagnostic and prognostic applications, including miRNA signatures capable of discriminating RCC subtypes and circulating ncRNAs as minimally invasive biomarkers. Moreover, the manuscript discusses ncRNA-mediated mechanisms of resistance to targeted therapies such as sunitinib, sorafenib, and axitinib, emphasizing regulatory networks involving miRNA targets, lncRNA-miRNA sponging, RNA-binding proteins, extracellular vesicle transfer, and epigenetic modulation. Emerging therapeutic opportunities are also addressed, including strategies aimed at inhibiting oncogenic ncRNAs or restoring tumor-suppressive ncRNAs to enhance drug sensitivity and improve patient stratification.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 2","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13010606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-02-18DOI: 10.3390/ncrna12010007
Alma D Campos-Parra, Jonathan Puente-Rivera, César López-Camarillo, Stephanie I Nuñez-Olvera, Nereyda Hernández Nava, Gabriela Alvarado Macias, Macrina Beatriz Silva-Cázares
{"title":"The Stiff Side of Cancer: How Matrix Mechanics Rewrites Non-Coding RNA Expression Programs.","authors":"Alma D Campos-Parra, Jonathan Puente-Rivera, César López-Camarillo, Stephanie I Nuñez-Olvera, Nereyda Hernández Nava, Gabriela Alvarado Macias, Macrina Beatriz Silva-Cázares","doi":"10.3390/ncrna12010007","DOIUrl":"10.3390/ncrna12010007","url":null,"abstract":"<p><p>Extracellular matrix (ECM) stiffening is a defining biophysical feature of solid tumors that reshape gene regulation through mechanotransduction. Increased collagen crosslinking and stromal remodeling enhance integrin engagement, focal-adhesion signaling and force transmission to the nucleus, where key hubs such as lysyl oxidase (LOX), focal adhesion kinase (FAK) and the Hippo co-activators YAP1 and TAZ (WWTR1) promote proliferation, invasion, stemness and therapy resistance. Here, we synthesize evidence that quantitative changes in matrix stiffness remodel the miRNome and lncRNome in both tumor and stromal compartments, including extracellular vesicle cargo that reprograms metastatic niches. To address heterogeneity in experimental support, we classify mechanosensitive ncRNAs into studies directly validated by stiffness manipulation (e.g., tunable hydrogels/AFM) versus indirect associations based on mechanosensitive signaling, and we summarize physiological versus pathophysiological stiffness ranges across tissues discussed. We further review competing endogenous RNA (ceRNA) networks converging on mechanotransduction nodes and ECM remodeling enzymes, and discuss translational opportunities and challenges, including targeting mechanosensitive ncRNAs, combining ncRNA modulation with anti-stiffening strategies, delivery barriers in dense tumors, and the potential of circulating/exosomal ncRNAs as biomarkers. Overall, integrating ECM mechanics with ncRNA regulatory circuits provides a framework to identify feed-forward loops sustaining aggressive phenotypes in rigid microenvironments and highlights priorities for validation in physiologically relevant models.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12943065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147290600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-02-11DOI: 10.3390/ncrna12010006
Christopher Klapproth, Franziska Reinhardt, Peter F Stadler, Sven Findeiß
{"title":"Computational Analysis of Telomerase RNA Evolution in <i>Caenorhabditis</i> Species.","authors":"Christopher Klapproth, Franziska Reinhardt, Peter F Stadler, Sven Findeiß","doi":"10.3390/ncrna12010006","DOIUrl":"10.3390/ncrna12010006","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The telomerase RNA (TR) is an indispensable part of the telomerase protein complex responsible for telomere elongation in most eukaryotic species. Although the telomere terminal repeat sequence (TTAGGC)<sub>n</sub> in <i>Caenorhabditis elegans</i> has been known for years, a telomerase RNA gene was not identified in the entire phylum of Nematoda until recently. <b>Methods:</b> In this exploratory study, we employ a combination of different approaches to identify likely telomerase RNA candidates among putative non-coding transcripts. <b>Results:</b> A detailed analysis of our prime candidate shows compelling evidence that it encodes the missing RNA element of the telomerase complex, which is notably located in an intron of the coding gene <i>nmy-2</i>. Using <i>nmy-2</i> homologs in other nematodes as anchors, we annotate the conserved TR gene in 21 <i>Caenorhabditis</i> species. We furthermore show that the intronic localization of the TR gene is conserved in two distinct branching groups of the <i>Caenorhabditis</i> phylogeny and demonstrate that this property likely emerged from a single point of origin. <b>Conclusions:</b> While the intronic TR represents a very interesting evolutionary adaption that seems to have been successful in the Elegans and Japonica groups, the question regarding the macroscopic nematode TR evolution remains.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146259006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-02-09DOI: 10.3390/ncrna12010005
Clara Claus, Carla Borini Etichetti, Bruno Costa, Julieta B Grosso, Juan Pablo Tosar, Uciel Chorostecki, Silvana V Spinelli
{"title":"Extracellular Small RNAs in Human Milk: Molecular Profiles, Stability and Fragment-Specific Responses in Cell-Based Assays.","authors":"Clara Claus, Carla Borini Etichetti, Bruno Costa, Julieta B Grosso, Juan Pablo Tosar, Uciel Chorostecki, Silvana V Spinelli","doi":"10.3390/ncrna12010005","DOIUrl":"10.3390/ncrna12010005","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Human milk is a complex biological fluid containing not only macro- and micronutrients but also diverse bioactive molecules, including extracellular RNAs. Although RNA has been detected in milk for decades, only a subset of RNA species has been characterized in detail, and abundant families such as tRNA-, yRNA-, and rRNA-derived fragments remain underexplored. This study aimed to define the composition, fragmentation patterns, stability, and exploratory functional activity of these highly abundant RNAs in human milk. <b>Methods:</b> We performed small RNA sequencing on skim milk samples and analyzed the resulting profiles in comparison with publicly available milk and biofluid datasets. RNA stability assays, Northern blotting, and RT-qPCR were conducted to validate RNA abundance and degradation kinetics. Extracellular vesicles (EVs) and non-vesicular fractions were analyzed to determine the subcellular distribution of RNA species. Exploratory functional assays using synthetic RNA fragments were carried out to assess their ability to modulate cellular responses in vitro. <b>Results:</b> Human milk was found to be highly enriched in small RNA fragments derived from tRNA, yRNA, and rRNA, dominated by a limited set of discrete sequences. These profiles were highly reproducible across independent datasets and distinct biofluids. Orthologal validation assays confirmed their abundance and stability, with RNA levels exceeding those of serum by over two orders of magnitude. Full-length transcripts were enriched in EVs, whereas shorter fragments predominated in the non-vesicular fraction. Synthetic milk-derived exRNAs showed detectable pro-survival activity under stress conditions in vitro. <b>Conclusions:</b> This study reveals that human milk carries a limited set of highly abundant stable sRNA molecules, primarily derived from tRNAs, yRNAs, and rRNAs. These findings provide new insights into the RNA cargo of human milk and offer preliminary evidence that selected sRNA fragments can modulate cellular stress responses in in vitro models.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146258926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Non-Coding RNAPub Date : 2026-01-31DOI: 10.3390/ncrna12010004
Samuel J Gonzalez, Edgardo Linares, Allison M Porman Swain, Aaron M Johnson
{"title":"Mechanisms at the Intersection of lncRNA and m6A Biology.","authors":"Samuel J Gonzalez, Edgardo Linares, Allison M Porman Swain, Aaron M Johnson","doi":"10.3390/ncrna12010004","DOIUrl":"10.3390/ncrna12010004","url":null,"abstract":"<p><p>This review provides a thorough survey of long noncoding RNAs that bear the RNA modification N6-methyladenosine (m6A) and current work to understand the resulting mechanistic and biological consequences. We give an overview of lncRNA and m6A biology first, describing the writers, erasers, and readers of m6A and their targeting of lncRNAs. Next, we give an in-depth review of the field of nuclear lncRNAs that regulate chromatin and their regulation via m6A. We then describe the growing appreciation of liquid-liquid phase separation properties in lncRNA and m6A biology. Finally, we cover examples of cytoplasmic lncRNAs regulated by m6A. Overall, this review aims to emphasize how epitranscriptomics influences noncoding RNA mechanisms to provide additional layers of regulation, integrated into downstream biological processes.</p>","PeriodicalId":19271,"journal":{"name":"Non-Coding RNA","volume":"12 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}